4Z16

Crystal Structure of the Jak3 Kinase Domain Covalently Bound to N-(3-(((5-chloro-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)methyl)phenyl)acrylamide

Summary for 4Z16

• Entry DOI: 10.2210/pdb4z16/pdb
• Descriptor: Tyrosine-protein kinase JAK3, N-(3-{[(5-chloro-2-{[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)amino]methyl}phenyl)prop-2-enamide (3 entities in total)
• Functional Keywords: tyrosine kinase, kinase domain, covalent inhibitor complex, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Endomembrane system ; Peripheral membrane protein : P52333
• Total number of polymer chains: 4
• Total formula weight: 145875.42

Authors

McNally, R.,Tan, L.,Gray, N.S.,Eck, M.J. (deposition date: 2015-03-26, release date: 2016-02-10, Last modification date: 2024-11-13)

Primary citation

Tan, L.,Akahane, K.,McNally, R.,Reyskens, K.M.,Ficarro, S.B.,Liu, S.,Herter-Sprie, G.S.,Koyama, S.,Pattison, M.J.,Labella, K.,Johannessen, L.,Akbay, E.A.,Wong, K.K.,Frank, D.A.,Marto, J.A.,Look, T.A.,Arthur, J.S.,Eck, M.J.,Gray, N.S.
Development of Selective Covalent Janus Kinase 3 Inhibitors.
J.Med.Chem., 58:6589-6606, 2015

PubMed Abstract: The Janus kinases (JAKs) and their downstream effectors, signal transducer and activator of transcription proteins (STATs), form a critical immune cell signaling circuit, which is of fundamental importance in innate immunity, inflammation, and hematopoiesis, and dysregulation is frequently observed in immune disease and cancer. The high degree of structural conservation of the JAK ATP binding pockets has posed a considerable challenge to medicinal chemists seeking to develop highly selective inhibitors as pharmacological probes and as clinical drugs. Here we report the discovery and optimization of 2,4-substituted pyrimidines as covalent JAK3 inhibitors that exploit a unique cysteine (Cys909) residue in JAK3. Investigation of structure-activity relationship (SAR) utilizing biochemical and transformed Ba/F3 cellular assays resulted in identification of potent and selective inhibitors such as compounds 9 and 45. A 2.9 Å cocrystal structure of JAK3 in complex with 9 confirms the covalent interaction. Compound 9 exhibited decent pharmacokinetic properties and is suitable for use in vivo. These inhibitors provide a set of useful tools to pharmacologically interrogate JAK3-dependent biology.

PubMed: 26258521
DOI: 10.1021/acs.jmedchem.5b00710

Experimental method

X-RAY DIFFRACTION (2.9 Å)